Cocaine abuse by young men and women is a major public health problem today. A wide spectrum of medical disorders are associated with cocaine abuse and dependence including reproductive dysfunction (hyperprolactinemia, amenorrhea, luteal phase defects, male impotence); pregnancy abnormalities and impaired perinatal development; life threatening cerebrovascular and cardiovascular anomalies as well as compromised immune function which increases risk for infectious disease including AIDS. The proposed continuation of our NIDA Clinical Research Center, "Polydrug Abuse in Women" focuses upon the neuroendocrine consequences of cocaine abuse as well as the pre-clinical evaluation of new medications for treatment of cocaine abuse and polydrug abuse. Possible gender differences in vulnerability to cocaine's adverse biologic consequences will be assessed by inclusion of both male and female subjects. Scientific and congressional concerns have recently converged to emphasize the importance of studying women as well as men. We propose to conduct a parametric evaluation of the effects of chronic cocaine abuse and dependence on neuroendocrine hormones essential for normal reproductive function in parallel studies in women and in a primate model. Hyperprolactinemia is often associated with cocaine abuse and may compromise immune function. Cocaine stimulates adrenocorticotropin (ACTH) secretion which may subsequently modify immune function and susceptibility for infectious disease including AIDS. Computer-based pulse frequency analysis of ACTH, gonadotropin and prolactin secretory activity during cocaine abuse and cocaine abstinence will provide an index of hormonal impairment and capacity for recovery. Provocative tests of hypothalamic- pituitary-gonadal and adrenal function will be used to study the sites of cocaine's reproductive system toxicity. Controlled studies of the effectiveness of new medications in reducing drug self-administration in the primate model are also proposed. Females and males will be studied to assess possible gender differences in response to pharmacotherapy treatment. Established operant behavioral procedures will be used to evaluate the efficacy and safety of new pharmacotherapies on cocaine and heroin self-administration. A new model of polydrug abuse will be developed to simulate simultaneous cocaine and heroin ("speedball") self-administration. The effects of new pharmacotherapies on "speedball" self-administration will be evaluated. Drug discrimination procedures will be used to predict the therapeutic efficacy and the optimal dose range of new medications. These studies should facilitate clinical trials of new drug abuse treatments.